Divisions of General Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
Divisions of General Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Divisions of Gastroenterology and Hepatology, Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
Eur J Pharmacol. 2018 Apr 5;824:133-139. doi: 10.1016/j.ejphar.2018.02.016. Epub 2018 Feb 11.
Cirrhosis is often associated with portal hypertension and portal-systemic collateral vessels formation attributed to angiogenesis, which leads to severe complications as hepatic encephalopathy. Sirolimus has anti-fibrosis and anti-angiogenesis effects, but whether it influences the severity of portal-systemic collaterals and hepatic encephalopathy is unknown. This study was thus designed to address this issue in rats with common bile duct ligation-induced liver cirrhosis. Sham-operated rats were surgical controls. Rats were intraperitoneally administered with 0.5 and 2 mg/kg/day sirolimus or vehicle for 2 weeks. Four weeks post operations, motor activities, body weight, biochemistry and hemodynamic data were measured. The liver was dissected for histopathology, immunohistochemical stains and protein analysis. On the parallel cirrhotic groups, the portal-systemic shunting was determined. The results showed that the body weight gain was significantly lower in sirolimus-treated rats. Sirolimus reduced portal pressure and plasma levels of alanine aminotransferase, aspartate aminotransferase and ammonia, and attenuated hepatic inflammation and fibrosis in cirrhotic rats. In addition, the hepatic phosphorylated mammalian target of rapamycin (mTOR) and P70S6K protein expressions were significantly downregulated and endothelial nitric oxide synthase (eNOS) expression upregulated by sirolimus. Sirolimus did not influence portal-systemic shunting and motor activities of cirrhotic rats. In conclusion, sirolimus significantly improved hepatic inflammation and fibrosis accompanied by portal pressure reduction in cirrhotic rats, in which down-regulated mTOR/P70S6K and up-regulated eNOS expressions might play a role. However, sirolimus did not significantly change the severity of portal-systemic collaterals and motor activities, suggesting that the multifactorial pathogenesis of hepatic encephalopathy could not be fully overcome by sirolimus.
肝硬化常伴有门静脉高压和门体侧支循环形成，这归因于血管生成，导致肝性脑病等严重并发症。西罗莫司具有抗纤维化和抗血管生成作用，但它是否影响门体侧支循环和肝性脑病的严重程度尚不清楚。因此，本研究旨在探讨西罗莫司对胆总管结扎诱导的肝硬化大鼠的影响。假手术大鼠作为手术对照。大鼠腹腔内分别给予 0.5 和 2mg/kg/天西罗莫司或载体，持续 2 周。手术后 4 周，测量运动活动、体重、生化和血液动力学数据。解剖肝脏进行组织病理学、免疫组织化学染色和蛋白质分析。在平行的肝硬化组中，确定门体分流。结果显示，西罗莫司治疗组大鼠体重增长明显降低。西罗莫司降低了门静脉压力和血浆丙氨酸氨基转移酶、天冬氨酸氨基转移酶和氨水平，并减轻了肝硬化大鼠的肝炎症和纤维化。此外，西罗莫司显著下调了肝磷酸化哺乳动物雷帕霉素靶蛋白（mTOR）和 P70S6K 蛋白表达，并上调了内皮型一氧化氮合酶（eNOS）表达。西罗莫司对肝硬化大鼠的门体分流和运动活动没有影响。总之，西罗莫司显著改善了肝硬化大鼠的肝炎症和纤维化，同时降低了门静脉压力，其中下调 mTOR/P70S6K 和上调 eNOS 表达可能起作用。然而，西罗莫司并没有显著改变门体侧支循环和运动活动的严重程度，这表明肝性脑病的多因素发病机制不能完全被西罗莫司克服。
